12-121167552-G-A

Variant names:

• chr12-121167552-G-A
• rs7958311
• NM_002562.6:c.809G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002562.6(P2RX7):​c.809G>A​(p.Arg270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,612,774 control chromosomes in the GnomAD database, including 51,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R270C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5164 hom., cov: 31)
  • Exomes 𝑓: 0.25 (46181 hom.)
• Consequence: P2RX7 NM_002562.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.413

Genes affected

P2RX7 (HGNC:8537): (purinergic receptor P2X 7) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel and is responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Activation of this nuclear receptor by ATP in the cytoplasm may be a mechanism by which cellular activity can be coupled to changes in gene expression. Multiple alternatively spliced variants have been identified, most of which fit nonsense-mediated decay (NMD) criteria. [provided by RefSeq, Jul 2010]

LOC105370032 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.839799E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX7	NM_002562.6	c.809G>A	p.Arg270His	missense_variant	Exon 8 of 13	ENST00000328963.10	NP_002553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX7	ENST00000328963.10	c.809G>A	p.Arg270His	missense_variant	Exon 8 of 13	1	NM_002562.6	ENSP00000330696.6

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39039 AN: 151776 Hom.: 5164 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.268

GnomAD2 exomes AF: 0.247 AC: 61873 AN: 250430 AF XY: 0.240

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.247 AC: 360703 AN: 1460880 Hom.: 46181 Cov.: 33 AF XY: 0.243 AC XY: 176741 AN XY: 726790

Gnomad4 AFR exome AF: 0.238 AC: 7943 AN: 33432

Gnomad4 AMR exome AF: 0.258 AC: 11495 AN: 44622

Gnomad4 ASJ exome AF: 0.290 AC: 7576 AN: 26098

Gnomad4 EAS exome AF: 0.390 AC: 15459 AN: 39592

Gnomad4 SAS exome AF: 0.110 AC: 9474 AN: 86194

Gnomad4 FIN exome AF: 0.221 AC: 11809 AN: 53400

Gnomad4 NFE exome AF: 0.252 AC: 280200 AN: 1111440

Gnomad4 Remaining exome AF: 0.255 AC: 15394 AN: 60342

GnomAD4 genome AF: 0.257 AC: 39047 AN: 151894 Hom.: 5164 Cov.: 31 AF XY: 0.257 AC XY: 19048 AN XY: 74238

Gnomad4 AFR AF: 0.246 AC: 0.246376 AN: 0.246376

Gnomad4 AMR AF: 0.298 AC: 0.297902 AN: 0.297902

Gnomad4 ASJ AF: 0.300 AC: 0.3 AN: 0.3

Gnomad4 EAS AF: 0.421 AC: 0.421329 AN: 0.421329

Gnomad4 SAS AF: 0.118 AC: 0.118001 AN: 0.118001

Gnomad4 FIN AF: 0.226 AC: 0.226445 AN: 0.226445

Gnomad4 NFE AF: 0.253 AC: 0.253172 AN: 0.253172

Gnomad4 OTH AF: 0.265 AC: 0.265152 AN: 0.265152

Alfa AF: 0.256 Hom.: 17049

Bravo AF: 0.269

TwinsUK AF: 0.247 AC: 915

ALSPAC AF: 0.255 AC: 984

ESP6500AA AF: 0.239 AC: 1054

ESP6500EA AF: 0.247 AC: 2128

ExAC AF: 0.244 AC: 29607

Asia WGS AF: 0.240 AC: 833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.26	T
REVEL	Benign	0.064
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.060
ClinPred		0.019	T
GERP RS		0.97
Varity_R		0.073
gMVP		0.48
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7958311; hg19: chr12-121605355; COSMIC: COSV55853753; COSMIC: COSV55853753;